The long-term goal of this project is to understand the consequences of synaptic of cotransmission for information processing in sympathetic ganglia. Isolated preparations of bullfrog paravertebral sympathetic ganglia will be used for electrophysiological studies of muscarinic and peptidergic mechanisms that are co-activated by stimulation of preganglionic nerves and serve to modulate nicotinic transmission. The bullfrog system has been chosen because of its relatively simple and well-defined organization. Ganglion cells display 2 major phenotypes: B neurons innervate cutaneous glands and C neurons innervate arteries. Recent experiments indicate that interactions between subthreshold nicotinic EPSPs and modulatory synaptic events play a central role in ganglionic integration. These interactions have been previously overlooked because, under the conditions used in most cellular studies, they are overshadowed by strong suprathreshold nicotinic synapses. The proposed experiments have been designed to analyze subthreshold EPSPs in a manner that is relevant to normal in vivo patterns of asynchronous preganglionic activity. The Aims of the proposal are focused on 3 specific questions: 1) What are the integrative consequences of synaptic convergence in ganglia?, 2) What are the integrative consequences of presynaptic inhibition in ganglia?. 3) What is the mechanism for modulation of muscarinic and peptidergic cotransmission by the drug nicotine?. A fourth aim is to develop a mathematical model of ganglionic integration and fit it to the experimental data collected for aims 1 and 2. The goal is to explore dynamic properties of cotransmission that can not be directly observed through experiment and to develop testable predictions of postganglionic firing, in vivo. This project will provide fundamental new information about cellular mechanisms of synaptic cotransmission and a formalism for generalizing the results form a simple model system to mammalian systems. The nicotine experiments are important because they may define the primary cellular mechanism mediating the peripheral autonomic effects of smoking.